At the request of the EMA (European Medicines Agency), Marketing Authorization Holders (MAH) are required to monitor the presence of nitrosamines in their medicines, by presenting, among other things, an assessment of the potential contamination risks. This evaluation must be done before March 26th 2020 in France and before May 15th 2020 in Switzerland.
Nitrosamines classified as “dangerous” found in certain medicines
Chemical reactions between amines, ammonia salts and nitrites, cross contaminations, the use of contaminated ingredients, packaging, cleaning protocols… potential sources of nitrosamines are numerous and widespread.
Classified as, or suspected to be carcinogens, European and American markets have more than once had to carry out mass recalls of medicines designed for human consumption containing trace amounts of nitrosamines
In 2018, the EMA lead investigations and information campaigns with the support of competent authorities to reduce the risk of nitrosamines being present in pharmaceutical products. In September of 2019, the EMA and the CMD published a document titled “Information on nitrosamines for marketing authorization holders” detailing the importance of evaluating the risk of nitrosamine contaminations during production processes.
New requirements are also added to the responsibilities of MAHs for the inspection of impurities as well as of active ingredients and some other components (dyes, solvents, catalysts…).
Steps to follow :
In this regard, measures must be implemented quickly, following these steps :
Step 1 : Risk assessment and management in accordance with ICH Q9 guidelines
- Classification of APIs and medicines by priority (daily dose, treatment duration, route of administration, patient profile…)
- Determination of the risk of potential nitrosamine contaminations depending on the production process
- Detailed conclusions on the presence of absence of a risk
The EMA has asked for a report on these evaluations before March 26th 2020
SWISSMEDIC set their deadline to May 15th 2020.
Step 2 : Confirmation tests
If a potential risk has been identified, analysis must be carried out in the order set in the first step, sorting by priority and in accordance with the following requirements :
- The analytical methods must be validated
- LoQ must be under 30 ppb
- The analysis being carried out must comply with GMP
Authorities will have to be informed if the results reveal that nitrosamines are present, whatever the amount may be.
Step 3 : Implementation of corrective procedures
Corrective procedures (a change in the production process, a change in the supplier’s scope statement…) will need to be implemented before September 26 2022, 3 years after the EMA published their document and November 15th 2021, 2 years after SWISSMEDIC published theirs.
FILAB : providing specific services for evaluating the risks of nitrosamine contamination
To assist producers in developing and controlling the quality of their product, while complying with the changes in regulations mentioned above, FILAB laboratory provides its cutting-edge analytical fleet making it possible to detect and quantify nitrosamines (NDMA, NDEA, NDMEA, NDPA…) and their precursors in samples.
The limits of detection for determining nitrosamine contents vary from 1 to 10 µk/kg depending on the nitrosamine and matrix being used.
It is important to note that FILAB uses many methods which have been validated by COFRAC, a member of ILAC, for determining nitrosamine contents using LC-MS/MS.
FILAB also provides other services that can fulfil your needs relating to nitrosamines :
